Cerebrospinal fluid changes in autism

CSF

This is the normal fluid that is produced within the brain, largely derived from the fluid of the blood but its chemical content is very much a separate factor. The blood-brain barrier that separates the brain from the blood only permits specific relatively smaller molecules to penetrate into the CSF. The CSF has a continuous turnover such that the proteins and smaller molecules that are present are continuously being lost into the blood and new ones replace them. As such CSF has a very specific chemical make up and is changed in around 24hrs.

CSF in autism

To get CSF samples from autistic children is always difficult in that there is a small but present risk to the child in taking the fluid through a needle. Because of this the child often must have a specific reason for the CSF sample to be taken and hence may have symptoms that they did not generally have e.g. started to show epileptic fits. Because of this the testing of CSF is always difficult to interpret as any changes may not be due to the autism but to the new condition for which the sample is taken. The researchers have tried hard to avoid this problem.

Changes seen

No increase in white cells, changes in standard blood proteins, or sugars are reported. However specific alterations have been seen:

Inflammatory markers
Metabolites and transmitters
Indicator of gliosis
Infection

CSF is produced in the choroid plexus and spreads throughout the ventricles before leaking into the blood in one way passages. It is shown in light blue

Inflammatory markers

Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007 Jun;36(6):361-5.

Riikonen R, Makkonen I, Vanhala R, Turpeinen U, Kuikka J, Kokki H. Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism. Dev Med Child Neurol. 2006 Sep;48(9):751-5. low concentrations of CSF IGF-1 at an early age might be linked with the pathogenesis in autism because IGF-1 is important for the survival of Purkinje cells

Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304. (Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1.) NB CSF samples taken post mortem.

Tani Y, Fernell E, Watanabe Y, Kanai T, Långström B. Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients. Neurosci Lett. 1994 Nov 7;181(1-2):169-72. (Among pterin compounds 7,8-dihydroneopterin (NH2) and 6R-5,6,7,8-tetrahydrobiopterin (R-BH4) levels in autistic children were significantly reduced to 66.1 and 41.5%, respectively, of those found in the controls.) (see Komori-H showing that there were no significant differences between responders, nonresponders, and controls in the CSF levels of the metabolites before R-THBP administration orally).

Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien S, Varsou A, Heyes MP. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol. 2005 Sep;33(3):195-201. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased, and biopterin (P = 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated (P<0.02).

Toda Y, Mori K, Hashimoto T, Miyazaki M, Nozaki S, Watanabe Y, Kuroda Y, Kagami S. Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103. Also association between improvement in symptoms and changes in the cerebrospinal fluid (CSF) homovanillic acid (HVA),5-hydroxyindole-3-acetic acid (5-HIAA), and 6R-5,6,7,8-tetrahydro-L-biopterin (BH(4)) levels after administration.

Metabolites and transmitters

Winsberg BG, Sverd J, Castells S, Hurwic M, Perel JM. Estimation of monoamine and cyclic-AMP turnover and amino acid concentrations of spinal fluid in autistic children. Neuropediatrics. 1980 Aug;11(3):250-5. ( CSF cyclic adenosine monophosphate (cAMP) was been found to be elevated in autistic children. They put it down to brain metabolism. )

Ignatova N, Sindic CJ, Goffinet AM. Characterization of the various forms of the Reelin protein in the cerebrospinal fluid of normal subjects and in neurological diseases. Neurobiol Dis. 2004 Mar;15(2):326-30. (In the adult brain, Reelin, a large glycoprotein, is expressed in a subset of GABAergic interneurons. Its role in disease states is not clearly defined, although it is implicated in autism and psychoses such as schizophrenia. In this report, they show that Reelin immunoreactive proteins can be detected in the human cerebrospinal fluid (CSF) with monoclonal antibodies directed against the N- and C-terminal regions of the protein but the interpretation of this is difficult . See reelin page)

Banks WA, Goulet M, Rusche JR, Niehoff ML, Boismenu R. Differential transport of a secretin analog across the blood-brain and blood-cerebrospinal fluid barriers of the mouse. J Pharmacol Exp Ther. 2002 Sep;302(3):1062-9. (just shows that it crosses the blood brain barrier more than other molecules of a similar size)

Vanhala R, Turpeinen U, Riikonen R. Low levels of insulin-like growth factor-I in cerebrospinal fluid in children with autism. Dev Med Child Neurol. 2001 Sep;43(9):614-6. (post mortem samples)

Riikonen R, Vanhala R. Levels of cerebrospinal fluid nerve-growth factor differ in infantile autism and Rett syndrome. Dev Med Child Neurol. 1999 Mar;41(3):148-52. (Normal nerve-growth factor in autism but very low levels in Rett’s)

Nagamitsu S, Matsuishi T, Kisa T, Komori H, Miyazaki M, Hashimoto T, Yamashita Y, Ohtaki E, Kato H. CSF beta-endorphin levels in patients with infantile autism. J Autism Dev Disord. 1997 Apr;27(2):155-63. (We measured CSF levels of beta-endorphin, an opioid hormone, in 19 patients with infantile autism and in 3 patients with Rett syndrome, and compared them with control values. In infantile autism, CSF levels of beta-endorphin did not differ significantly from those of age-matched controls). Several earlier articles discuss a change in beta-endorphins but they disagree and use lower numbers of samples. See Pub Med under autism and CSF.

Narayan M, Srinath S, Anderson GM, Meundi DB. Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry. 1993 Apr 15-May 1;33(8-9):630 (These data suggest that consistent, marked alterations in central serotonin and dopamine turnover are not present in the autistic subjects studied.)

Gliosis?

Ahlsén G, Rosengren L, Belfrage M, Palm A, Haglid K, Hamberger A, Gillberg C. Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Biol Psychiatry. 1993 May 15;33(10):734-43. (The results were contrasted with those obtained in similarly aged cases with other neuropsychiatric disorders (n = 25) and in normal children (n = 10). S-100 did not discriminate the groups from each other. However, GFA in autism and autistic-like conditions was at a level almost three times that in the normal group. The results could implicate gliosis and unspecific brain damage in autism).

Infection?: measles

Bradstreet JJ, Dahr J El, Anthony A, Kartzinel J, Wakefield AJ, Detection of meascles virus genomic RNA in Cerebrospinal fluid of children with regressive autism: a report of three cases. J Am Physicians and Surgeons 2004;9:38-45. (They looked for the measles virus genome RNA in the CSF of 3 of 3 autistic cases, only 2 of 3 had antibodies to measles in the CSF to measles. They suggest that this indicates a possibility of a virally driven cerebral immunopathology in some cases of regressive autism. None of the controls had the positive test for measles RNA)

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